Medicine (RMH) - Research Publications

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    Longitudinal Asthma Phenotypes from Childhood to Middle-Age A Population-based Cohort Study
    Tan, DJ ; Lodge, CJ ; Walters, EH ; Lowe, AJ ; Bui, DS ; Bowatte, G ; Pham, J ; Erbas, B ; Hui, J ; Hamilton, GS ; Thomas, PS ; Hew, M ; Washko, G ; Wood-Baker, R ; Abramson, MJ ; Perret, JL ; Dharmage, SC (AMER THORACIC SOC, 2023-07-15)
    Rationale: Asthma is a heterogeneous condition, and longitudinal phenotyping may provide new insights into the origins and outcomes of the disease. Objectives: We aimed to characterize the longitudinal phenotypes of asthma between the first and sixth decades of life in a population-based cohort study. Methods: Respiratory questionnaires were collected at seven time points in the TAHS (Tasmanian Longitudinal Health Study) when participants were aged 7, 13, 18, 32, 43, 50, and 53 years. Current-asthma and ever-asthma status was determined at each time point, and group-based trajectory modeling was used to characterize distinct longitudinal phenotypes. Linear and logistic regression models were fitted to investigate associations of the longitudinal phenotypes with childhood factors and adult outcomes. Measurements and Main Results: Of 8,583 original participants, 1,506 had reported ever asthma. Five longitudinal asthma phenotypes were identified: early-onset adolescent-remitting (40%), early-onset adult-remitting (11%), early-onset persistent (9%), late-onset remitting (13%), and late-onset persistent (27%). All phenotypes were associated with chronic obstructive pulmonary disease at age 53 years, except for late-onset remitting asthma (odds ratios: early-onset adolescent-remitting, 2.00 [95% confidence interval (CI), 1.13-3.56]; early-onset adult-remitting, 3.61 [95% CI, 1.30-10.02]; early-onset persistent, 8.73 [95% CI, 4.10-18.55]; and late-onset persistent, 6.69 [95% CI, 3.81-11.73]). Late-onset persistent asthma was associated with the greatest comorbidity at age 53 years, with increased risk of mental health disorders and cardiovascular risk factors. Conclusions: Five longitudinal asthma phenotypes were identified between the first and sixth decades of life, including two novel remitting phenotypes. We found differential effects of these phenotypes on risk of chronic obstructive pulmonary disease and nonrespiratory comorbidities in middle age.
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    Characterization of Patients in the International Severe Asthma Registry with High Steroid Exposure Who Did or Did Not Initiate Biologic Therapy.
    Chen, W ; Sadatsafavi, M ; Tran, TN ; Murray, RB ; Wong, CBN ; Ali, N ; Ariti, C ; Garcia Gil, E ; Newell, A ; Alacqua, M ; Al-Ahmad, M ; Altraja, A ; Al-Lehebi, R ; Bhutani, M ; Bjermer, L ; Bjerrum, AS ; Bourdin, A ; Bulathsinhala, L ; von Bülow, A ; Busby, J ; Canonica, GW ; Carter, V ; Christoff, GC ; Cosio, BG ; Costello, RW ; FitzGerald, JM ; Fonseca, JA ; Yoo, KH ; Heaney, LG ; Heffler, E ; Hew, M ; Hilberg, O ; Hoyte, F ; Iwanaga, T ; Jackson, DJ ; Jones, RC ; Koh, MS ; Kuna, P ; Larenas-Linnemann, D ; Lehmann, S ; Lehtimäki, LA ; Lyu, J ; Mahboub, B ; Maspero, J ; Menzies-Gow, AN ; Sirena, C ; Papadopoulos, N ; Papaioannou, AI ; Pérez de Llano, L ; Perng, D-W ; Peters, M ; Pfeffer, PE ; Porsbjerg, CM ; Popov, TA ; Rhee, CK ; Salvi, S ; Taillé, C ; Taube, C ; Torres-Duque, CA ; Ulrik, CS ; Ra, SW ; Wang, E ; Wechsler, ME ; Price, DB (Informa UK Limited, 2022)
    BACKGROUND: Many severe asthma patients with high oral corticosteroid exposure (HOCS) often do not initiate biologics despite being eligible. This study aimed to compare the characteristics of severe asthma patients with HOCS who did and did not initiate biologics. METHODS: Baseline characteristics of patients with HOCS (long-term maintenance OCS therapy for at least 1 year, or ≥4 courses of steroid bursts in a year) from the International Severe Asthma Registry (ISAR; https://isaregistries.org/), who initiated or did not initiate biologics (anti-lgE, anti-IL5/5R or anti-IL4R), were described at the time of biologic initiation or registry enrolment. Statistical relationships were tested using Pearson's chi-squared tests for categorical variables, and t-tests for continuous variables, adjusting for potential errors in multiple comparisons. RESULTS: Between January 2015 and February 2021, we identified 1412 adult patients with severe asthma from 19 countries that met our inclusion criteria of HOCS, of whom 996 (70.5%) initiated a biologic and 416 (29.5%) did not. The frequency of biologic initiation varied across geographical regions. Those who initiated a biologic were more likely to have higher blood eosinophil count (483 vs 399 cells/µL, p=0.003), serious infections (49.0% vs 13.3%, p<0.001), nasal polyps (35.2% vs 23.6%, p<0.001), airflow limitation (56.8% vs 51.8%, p=0.013), and uncontrolled asthma (80.8% vs 73.2%, p=0.004) despite greater conventional treatment adherence than those who did not start a biologic. Both groups had similar annual asthma exacerbation rates in the previous 12 months (5.7 vs 5.3, p=0.147). CONCLUSION: Around one third of severe HOCS asthma patients did not receive biologics despite a similar high burden of asthma exacerbations as those who initiated a biologic therapy. Other disease characteristics such as eosinophilic phenotype, serious infectious events, nasal polyps, airflow limitation and lack of asthma control appear to dictate biologic use.
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    Diagnosis of vocal cord dysfunction / inducible laryngeal obstruction-A Delphi study protocol.
    Leong, P ; Vertigan, AE ; Hew, M ; Baxter, M ; Phyland, D ; Hull, JH ; Carroll, TL ; Gibson, PG ; McDonald, VM ; Bardin, PG ; Silva, MT (Public Library of Science (PLoS), 2022)
    INTRODUCTION: Currently there is no consistent and widely accepted approach to the diagnosis of vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO). Harmonised diagnostic methods are vital to enable optimal diagnosis, advance management and enable research. We aim to obtain consensus on how expert clinicians recognise and diagnose VCD/ILO. METHODS AND ANALYSIS: Two-round modified Delphi, with workshop validation. ETHICS AND DISSEMINATION: Institutional Board Review was obtained from the Monash Health Human Research Ethics Committee. The dissemination plan is for presentation and publication. REGISTRATION DETAILS: Registered at Australia and New Zealand Clinical Trials Registry ACTRN12621001520820p.
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    Phenotypic Distinctions Between Omega-5-Gliadin Allergy and Peanut Allergy: Clinical Profile, Reaction Rates and Triggers, and Quality of Life.
    Zubrinich, CM ; Puy, RM ; O'Hehir, RE ; Hew, M (Informa UK Limited, 2022)
    BACKGROUND: Different phenotypes of food allergy may exist, exhibiting distinct clinical features, and driven by different pathogenic mechanisms. We compared omega-5-gliadin (O5G) allergy to peanut allergy, focusing on clinical features, reaction rates and triggers, and quality of life (QOL). METHODS: We surveyed adults with O5G allergy and peanut allergy regarding their diagnosis, co-morbidities, allergic reactions, and QOL measured by the FAQLQ-AF. RESULTS: We received responses from 43/80 (54%) individuals with O5G allergy and 43/130 (33%) with peanut allergy. Compared to peanut allergic individuals, those with O5G allergy were older at age of onset (37.2 vs 2.5 years, p < 0.001), had fewer additional atopic conditions (0.88 vs 2.93, p < 0.001) or food allergies (0.15 vs 1.86, p < 0.001), and more frequent reactions before diagnosis (1.085 vs 0.29 per month, p < 0.05) Reaction rates improved in both groups following diagnosis. Reactions to peanut were more often triggered by accidental exposure (84% vs 26%, p < 0.001) and being away from home (65% vs 28%, p < 0.001), while reactions to O5G were more often due to deliberate ingestion (30% vs 9%, p < 0.05) or unexpected exercise (35% vs 2%, p < 0.001). Overall QOL score was similar between groups (4.2 in O5G allergy, 4.7 in peanut allergy, p = 0.12), but worse among women and those with additional food allergies. CONCLUSION: Phenotypic differences between O5G and peanut allergy support the development of different clinical approaches and the possibility of targeting distinct pathogenic mechanisms for prevention and treatment. Quality of life was impaired to a similar degree between groups.
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    Genetic ancestry is associated with asthma, and this could be modified by environmental factors. A systematic review
    Pham, J ; Bui, DS ; Lodge, CJ ; Abramson, MJ ; Lowe, AJ ; Li, S ; Win, AK ; Hew, M ; Dharmage, SC (WILEY, 2023-06)
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    Regional variation in prevalence of difficult-to-treat asthma and oral corticosteroid use for patients in Australia: heat map analysis.
    Wark, PAB ; Hew, M ; Xu, Y ; Ghisla, C ; Nguyen, T-M ; Erdemli, B ; Samant, A ; Nan, C (Informa UK Limited, 2023-04)
    BACKGROUND: In Australia, the regional prevalence of difficult-to-treat asthma is unknown. We aimed to describe regional variation in difficult-to-treat asthma prevalence and oral corticosteroid (OCS) use. METHODS: In this retrospective, observational, longitudinal study using data from March 2018-February 2019 in the NostraData longitudinal database, prescriptions dispensed for obstructive airway disease were processed through a high-level algorithm to identify patients with asthma. Difficult-to-treat asthma was defined by ≥2 high-dosage inhaled corticosteroids plus long-acting beta-agonist prescriptions over 6 months. Patients who additionally received OCS prescriptions sufficient to treat ≥2 exacerbations over 6 months were classified as having uncontrolled difficult-to-treat asthma. Patient-level data were analyzed across 340 geographic areas in Australia to determine regional prevalence of difficult-to-treat asthma, uncontrolled difficult-to-treat asthma, and OCS use. RESULTS: Of 1 851 129 people defined as having asthma, 440 800 (24%) were classified as having difficult-to-treat disease. Of those difficult-to-treat asthma patients, 96 338 (22%) were considered to have uncontrolled disease. Between 29% and 48% of patients had difficult-to-treat asthma in 49 geographic areas, most frequently located in Western Australia. Between 26% and 67% of patients had uncontrolled difficult-to-treat asthma in 29 geographic areas (mostly in Eastern Australia). Overall, a wide variability of asthma severity and control was observed among regions. CONCLUSIONS: Despite global and national guidelines, regional differences in the prevalence of difficult-to-treat asthma and uncontrolled difficult-to-treat asthma and OCS use exist in Australia. Understanding these regional variations should inform policy and target management in the areas with the greatest unmet need.
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    RNA sequencing of single allergen-specific memory B cells after grass pollen immunotherapy: Two unique cell fates and CD29 as a biomarker for treatment effect
    McKenzie, C ; Varese, N ; Aui, PM ; Reinwald, S ; Wines, BD ; Hogarth, PM ; Thien, F ; Hew, M ; Rolland, JM ; O'Hehir, RE ; van Zelm, MC (WILEY, 2023-03)
    BACKGROUND: Sublingual immunotherapy (SLIT) for grass pollen allergy can modify the natural history of allergic rhinitis and is associated with increased allergen-specific IgG4 . IgG4 competitively inhibits functional IgE on the surface of effector cells, such as mast cells and basophils, from binding to allergens. To further understand the important role memory B-cell (Bmem) responses play in mediating the beneficial effects of SLIT, we assessed changes in allergen-specific Bmem subsets induced by SLIT for grass pollen allergy. METHODS: Blood samples were collected twice outside the pollen season from twenty-seven patients with sensitization to ryegrass pollen (RGP; Lolium perenne) and seasonal rhinoconjunctivitis. Thirteen received 4-month pre-seasonal SLIT for grass pollen allergy, and 14 received standard pharmacotherapy only. Single-cell RNA sequencing was performed on FACS-purified Lol p 1-specific Bmem before and after SLIT from four patients, and significant genes were validated by flow cytometry on the total cohort. RESULTS: Four months of SLIT increased RGP-specific IgE and IgG4 in serum and induced two Lol p 1-specific Bmem subsets with unique transcriptional profiles. Both subsets had upregulated expression of beta 1 integrin ITGB1 (CD29), whereas IGHE (IgE), IGHG4 (IgG4 ), FCER2 (CD23), and IL13RA1 were upregulated in one subset. There was an increase in the proportion of Lol p 1+ Bmem expressing surface IgG4 , CD23, and CD29 after SLIT. CONCLUSIONS: A clinically successful 4 months course of SLIT for grass pollen allergy induces two transcriptionally unique Bmem fates. Associated changes in surface-expressed proteins on these Bmem subsets can be used as early biomarkers for treatment effects.
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    Characterisation of the Australian Adult Population Living with Asthma: Severe - Exacerbation Frequency, Long-Term OCS Use and Adverse Effects.
    Hancock, KL ; Bosnic-Anticevich, S ; Blakey, JD ; Hew, M ; Chung, LP ; Cvetkovski, B ; Claxton, S ; Del Fante, P ; Denton, E ; Doan, J ; Ranasinghe, K ; Morgan, L ; Sharma, A ; Smith, PK ; Stewart, D ; Thompson, PJ ; Wiseman, R ; Upham, JW ; Yan, KY ; Carter, V ; Dhillon, K ; Heraud, F ; Le, T ; Vella, R ; Price, D ; OPCA Improving Asthma outcomes in Australia Research Group, (Informa UK Limited, 2022)
    INTRODUCTION: Asthma poses a significant burden for the Australian population. Understanding severe exacerbation rates, and steroid-related burden for adults diagnosed with asthma stands to offer insights into how this could be reduced. METHODS: Electronic medical records (EMR) and questionnaires from the Optimum Patient Care Research Database Australia (OPCRDA) were utilised retrospectively. OPCRDA is a real-world database with >800,000 medical records from Australian primary care practices. Outcomes were severe asthma exacerbations in Australian adults, over a 12-month period, stratified by Global Initiative for Asthma (GINA) treatment intensity steps, and steroid associated comorbidities. RESULTS: Of the 7868 adults treated for asthma, 19% experienced at least one severe exacerbation in the last 12-months. Severe exacerbation frequency increased with treatment intensity (≥1 severe exacerbation GINA 1 13%; GINA 4 23%; GINA 5a 33% and GINA 5b 28%). Questionnaire participants reported higher rates of severe exacerbations than suggested from their EMR (32% vs 23%) especially in steps 1, 4 and 5. Patients repeatedly exposed to steroids had an increased risk of osteoporosis (OR 1.95, 95% CI 1.43-2.66) and sleep apnoea (OR 1.78, 95% CI 1.30-2.46). CONCLUSION: The Australian population living with GINA 1, 4, 5a and 5b asthma have high severe exacerbation rates and steroid-related burden, especially when compared to other first world countries, with these patients needing alternative strategies or possibly specialist assessment to better manage their condition.
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    Reliability of the breathing pattern assessment tool for in-person or remote assessment in people with asthma.
    Bondarenko, J ; Hew, M ; Button, B ; Webb, E ; Jackson, V ; Clark, R ; Holland, AE (Wiley, 2021-09)
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    Severe asthma assessment, management and the organisation of care in Australia and New Zealand: expert forum roundtable meetings
    Maltby, S ; McDonald, VM ; Upham, JW ; Bowler, SD ; Chung, LP ; Denton, EJ ; Fingleton, J ; Garrett, J ; Grainge, CL ; Hew, M ; James, AL ; Jenkins, C ; Katsoulotos, G ; King, GG ; Langton, D ; Marks, GB ; Menzies-Gow, A ; Niven, RM ; Peters, M ; Reddel, HK ; Thien, F ; Thomas, PS ; Wark, PAB ; Yap, E ; Gibson, PG (WILEY, 2021-02)
    Severe asthma imposes a significant burden on individuals, families and the healthcare system. Treatment is complex, due to disease heterogeneity, comorbidities and complexity in care pathways. New approaches and treatments improve health outcomes for people with severe asthma. However, emerging multidimensional and targeted treatment strategies require a reorganisation of asthma care. Consensus is required on how reorganisation should occur and what areas require further research. The Centre of Excellence in Severe Asthma convened three forums between 2015 and 2018, hosting experts from Australia, New Zealand and the UK. The forums were complemented by a survey of clinicians involved in the management of people with severe asthma. We sought to: (i) identify areas of consensus among experts; (ii) define activities and resources required for the implementation of findings into practice; and (iii) identify specific priority areas for future research. Discussions identified areas of unmet need including assessment and diagnosis of severe asthma, models of care and treatment pathways, add-on treatment approaches and patient perspectives. We recommend development of education and training activities, clinical resources and standards of care documents, increased stakeholder engagement and public awareness campaigns and improved access to infrastructure and funding. Further, we propose specific future research to inform clinical decision-making and develop novel therapies. A concerted effort is required from all stakeholders (including patients, healthcare professionals and organisations and government) to integrate new evidence-based practices into clinical care and to advance research to resolve questions relevant to improving outcomes for people with severe asthma.